Abstract
BackgroundLiver transplantation (LT) is required in many end-stage liver diseases. Donation after cardiac death (DCD) livers are often used, and treatment of acute rejection (ACR) requires the use of immunosuppressive drugs that are associated with complications. Bone marrow mesenchymal stem cells (BMMSCs) are used in treatment following LT; however, they have limitations, including low colonization in the liver. An optimized BMMSC application method is required to suppress ACR.MethodsBMMSCs were isolated and modified with the heme oxygenase 1 (HO-1) gene. HO-1/BMMSCs were perfused into donor liver in vitro using a normothermic machine perfusion (NMP) system, followed by LT into rats. The severity of ACR was evaluated based on liver histopathology. Gene chip technology was used to detect differential gene expression, and flow cytometry to analyze changes in natural killer (NK) T cells.ResultsNMP induced BMMSCs to colonize the donor liver during in vitro preservation. The survival of HO-1/BMMSCs in liver grafts was significantly longer than that of unmodified BMMSCs. When the donor liver contained HO-1/BMMSCs, the local immunosuppressive effect was improved and prolonged, ACR was controlled, and survival time was significantly prolonged. The application of HO-1/BMMSCs reduced the number of NKT cells in liver grafts, increased the expression of NKT cell co-inhibitory receptors, and reduced NKT cell expression of interferon-γ.ConclusionsNK cell and CD8+ T cell activation was inhibited by application of HO-1/BMMSCs, which reduced ACR of transplanted liver. This approach could be developed to enhance the success rate of LT.
Highlights
Liver transplantation (LT) is required in many end-stage liver diseases
The rejection scores in the HMP and FK506 groups were significantly lower than those in the BMP group (P < 0.05); there was no significant difference between the HMP and FK506 groups (Fig. 2D). These results indicate that heme oxygenase 1 (HO-1)/Bone marrow mesenchymal stem cells (BMMSCs) combined with normothermic machine perfusion (NMP) preserved the Donation after cardiac death (DCD) livers in vitro, and HO-1/BMMSCs retained in the liver grafts after transplantation improved the pathology and inhibited acute rejection (ACR), similar to the level of FK506 application
Our findings demonstrate that BMMSCs infused via the portal vein using the NMP system can colonize the liver in large quantities
Summary
Liver transplantation (LT) is required in many end-stage liver diseases. Donation after cardiac death (DCD) livers are often used, and treatment of acute rejection (ACR) requires the use of immunosuppressive drugs that are associated with complications. Marginal donors are used for transplantation [2, 3], including donation after cardiac death (DCD) livers [4, 5]. Cao et al Stem Cell Research & Therapy (2021) 12:587 cold storage (SCS) methods are poor for preserving DCD livers, leading to increased probability of postoperative complications and affecting the prognosis of transplantation [4, 6]. The probability of acute rejection (ACR) remains 20–40% without the application of an effective immunosuppressive regimen following LT [7]. There is a need to explore effective immunomodulatory means to induce immune tolerance in LT, mitigate ACR, and decrease or avoid the use of immunosuppressive agents
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